A Race for Answers

FOR THE past 10 years, Rafat Abonour, MD, has run and cycled across Indiana to raise money for research related to multiple myeloma, an incurable cancer of plasma cells. While he’s covered more than 2,000 miles as part of his annual Miles for Myeloma fundraising event, the most important strides he’s made haven’t been on the roads.

Fueled by nearly $2.75 million donated by patients, families and other Miles for Myeloma supporters, Dr. Abonour and his colleagues in the multiple myeloma program at the Indiana University Melvin and Bren Simon Cancer Center have helped win approval of new drugs, developed methods to alleviate debilitating symptoms of the disease, and illuminated how myeloma hijacks the body’s normal systems.

Their work, combined with the efforts of researchers elsewhere, is paying off: Survival rates for myeloma have doubled in the last decade. But more must be done. The average patient still only lives a little more than seven years after symptoms develop.

“When you have a rare cancer and the cancer behaves differently in each patient, it is difficult to come up with a one-size-fits-all treatment,” says Dr. Abonour, a professor of medicine at the Indiana University School of Medicine. “What I mean is that we need to study each patient carefully so we can come up with the right treatment for each patient. That is why research is so important.”

Exactly what causes myeloma isn’t known, but something goes awry that makes plasma cells — key players in our immune systems — multiply out of control. Those cancerous cells primarily settle in bone marrow — the spongy tissue inside our bones — and crowd out the healthy cells our bodies need. The disease causes symptoms such as bone pain, kidney problems, weakness, infections and anemia.

Generally, myeloma is treated with chemotherapy and stem cell transplants, but the cancer inevitably comes back.“You feel like research is your last hope,” says Dana Holzapfel, a patient who travels from Greenville, Ohio, to be treated by Dr. Abonour and who recently participated in a clinical research trial at IU. “When you have cancer — anyone who has cancer — you don’t want to die, you want to live as long as you can and not have that looking over your shoulder constantly.” “It makes me feel good that the doctors there are doing the research,” she says of IU.

Building A Robust Research Program

About 24,000 Americans are diagnosed with myeloma each year, making it a relatively uncommon cancer that primarily affects people over age 65. Given that, lots of oncologists don’t see many myeloma cases. Dr. Abonour arrived at IU 13 years ago and was the first faculty member to focus on the disease. “I said, ‘Let’s build a program,’” he recalls. “We built it one patient at a time.”

Today, he and four colleagues treat myeloma through the School of Medicine’s clinical partnership with Indiana University Health. Together, Dr. Abonour, Attaya Suvannasankha, MD, Rebecca Silbermann, MD, Sherif Farag, MD, PhD, and G. David Roodman, MD, PhD, see approximately 400 new myeloma patients each year, and provide ongoing treatment and
monitoring to a total of 1,600 people.

In addition to the growth in its patient care program, IU has experienced a surge in research activity, with the annual Miles for Myeloma fundraiser providing vital funding needed to recruit scientists and seed their work.

The team’s goals are straightforward: to help patients live longer and better.

Improving Cancer Treatments

Many patients with active myeloma eventually undergo a stem cell transplant. The procedure involves collecting a patient’s healthy, blood-forming cells and storing them for later use. Then, high-dose chemotherapy is given to kill cancerous cells throughout the body. Finally, the healthy stem cells are infused back into the patient to replace the good cells that were also destroyed by the chemo.One theory as to why myeloma returns after a stem cell transplant is that patients aren’t given enough of the chemo drugs to get rid of all the cancer in their systems. The remaining cancer cells eventually multiply and overtake healthy cells once again.Dr. Suvannasankha, an assistant professor of clinical medicine, is conducting research using high doses of the drugs lenalidomide and melphalan before a stem cell transplant to determine if the combination improves the efficacy of the transplant. Lenalidomide, which is FDA-approved for myeloma, appears to have an additive cancer-killing effect when used with melphalan. The study is still ongoing, and the results are promising to date.

Dr. Farag is also investigating how to improve the results of stem cell transplants. Part of his focus is on allogeneic transplants, which involve taking stem cells from a different, healthy donor. These types of transplants are viewed as substantially riskier because of the potential for graft vs. host disease, a life-threatening complication in which the donor’s immune cells also attack the patient’s normal tissues. The threat is so great that allogeneic transplants are not commonly offered to myeloma patients in the United States outside of clinical trials.

But allogeneic transplants nonetheless hold promise, in that stem cells from someone else may be more effective than the patient’s own at fighting the cancer. So Dr. Farag, the Lawrence H. Einhorn Professor of Oncology, is studying how to improve the process. Based on the results of a laboratory study, he is using drugs to modify a patient’s immune system with the goal of reducing cells that might cause rejection and enhancing those that eradicate the cancer.

“This is still an important area of research because it is the only treatment today that can definitively cure myeloma,” Dr. Farag says.

These are just two examples of a long list of studies underway to improve treatments designed to combat myeloma. Across the board, IU physicians and researchers are testing new drugs and new combinations of drugs to identify the best treatments with the fewest possible side effects. And much of the work is happening only at IU, Dr. Abonour says.

A Better Quality of Life

As patients live longer with myeloma, researchers are also focused on ensuring they have the best quality of life possible. A top priority is to tackle bone disease, one of the most common and debilitating problems associated with the cancer.

Normally, our bones are constantly remodeling themselves to stay strong. Cells called osteoclasts
chew up old bone, and osteoblasts make new bone to replace what was lost. But myeloma hijacks this process. The cancer increases the activity of the chewers and suppresses the activity of the builders. That results in holes, or lesions, that form in and weaken the bone. There is no way to repair them, often leaving patients in terrible pain and at a high risk for devastating fractures
and breaks.

“Even if your myeloma is in remission, your bones never heal properly,” says Dr. Roodman, chief of the Division of Hematology/Oncology and the Kenneth Wiseman Professor of Medicine.

Historically, researchers have sought to address this problem by shutting down the over-active osteoclasts. While there has been success with that approach, simply stopping cells that destroy bone doesn’t help fill holes that have already formed.

Dr. Silbermann’s lab has been studying a protein that is elevated in myeloma patients and inhibits bone growth. She and her team discovered how to interfere with the protein by blocking certain receptors, and they’ve identified an experimental drug they believe will accomplish that. The drug, which is not yet FDA approved, has previously been shown to improve bone density in patients with osteoporosis, but it has not been tested in myeloma patients.

She plans to launch a clinical trial to test the drug against a placebo to see whether it spurs bone growth. Such a breakthrough would help more patients live without fear of a serious injury.

“These lesions affect quality of life,” explains Dr. Silbermann, an assistant professor of medicine who both treats patients and conducts laboratory research. “A lot of patients are always asking, ‘What can I do and what can’t I do?’ It limits them.”

Dr. Roodman is also conducting important work in this area. His laboratory is studying a specific inhibitor that stunts bone growth and is increased in myeloma patients. He and his team have recently found that blocking the inhibitor can kick start bone-building cells. In collaboration with scientists at the University of Pittsburgh, they have developed a new treatment that successfully increases bone formation in mice with myeloma. Ongoing studies in the Roodman lab are determining the potential for eventually using this treatment in patients.

PERSONALIZING CARE

Even as new drugs and treatment regimens are discovered, it is impossible to know which therapies will work best for individual patients. Patients must simply try them and hope for the best. That sometimes means suffering through brutal side effects without any benefit.

“People ask all the time, ‘Why can’t you use my cancer cells and do sensitivity testing,’” says Dr.
Suvannasankha.The answer, she explains, is that most myeloma cells won’t grow outside of the body. They need bone marrow to survive. In fact, when myeloma patients donate blood, the chances are slim that the cancerous cells would transfer to the recipient.

Myeloma cancer cell lines that are used for research are derived from unusually aggressive cells that do not behave like “real life” myeloma and do not require bone marrow for growth. Usually, early stage testing of new drugs requires transplanting myeloma cell lines into mice, waiting for the mice to develop myeloma, and then treating them with new drugs to see if they work. The steps are time-consuming and costly.

So Dr. Suvannasankha and her colleague, John Chirgwin, PhD, are pioneering a solution in the laboratory. They have found that placing myeloma cells on a section of mouse skull keeps them alive. But, just as importantly, the cells embed into the bone, causing lytic lesions, mimicking myeloma that we would see in a person. This has the potential to lead to significant breakthroughs:

• Scientists will be able to study in real-time how the cancerous cells grow in the bone and possibly identify new ways to attack them.
• Potential myeloma drugs can be tested rapidly to see if they are effective at killing the cancer and are therefore worth pursuing.
• Down the road, an individual’s myeloma cells could be screened to see which drugs will work best for him or her.

“We want to get effective enough at doing this to say, ‘Based on our platform, you’re better off using this drug or that drug or this combination of drugs,’ ” Dr. Suvannasankha says. “It could exclude things that won’t ever work.”

CONTINUING TO GROW

As a runner and cyclist, it should come as no surprise that Dr. Abonour isn’t satisfied staying in the same place for too long. His goal – shared by his colleagues – is to move the research forward, and to do it fast.

Their hope is to bring in more world-class researchers to help them study every aspect of myeloma. For instance, Dr. Abonour would like to recruit someone who is focused on myeloma and the immune system, and Dr. Roodman would like to add an expert on the tumor and genetic mutations that drive it.

One big question that lingers is why only about 1 percent of people with abnormal plasma cells go on to develop myeloma while the rest do not. Understanding the difference could be key to finding a cure.

But research is expensive, and attracting a star researcher and his or her team can cost millions of dollars. That is why Miles for Myeloma and ongoing gifts to support myeloma research are so important.

“I am proud of our team and optimistic about the future,” Dr. Abonour says. “We love to heal patients and we would love to cure them. We will never stop asking why multiple myeloma causes harm to patients, and we will explore the most effective treatments that will provide long and healthy lives for those afflicted by this horrible disease.”

To support Miles for Myeloma, contact Lizzie Conkle at econkle@iu.edu or 317-278-2120.